PROJECT SUMMARY Tauopathies are a class of neurodegenerative disorders associated with deposits of insoluble tau protein within the brain. At over 5 million cases currently diagnosed among Americans, Alzheimer?s disease (AD) is the most common type of tauopathy. With no therapies that significantly slow or alter the disease course for AD, the number of Americans diagnosed with AD is expected to increase to 16 million by the year 2050. As one of two hallmark pathologies of AD, pathogenic tau has emerged as a promising target for therapeutic targeting. Mutations in the tau gene are associated with dominantly inherited familial tauopathies termed frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), demonstrating that tau dysfunction is sufficient to drive neurodegeneration. The goal of this proposal is to understand the specific cellular processes that connect pathogenic tau to neurodegeneration in AD and related tauopathies, and to target these processes pharmacologically. An active cellular program maintains the terminally differentiated, post-mitotic state of neurons. When this program is perturbed, post-mitotic neurons can re- activate the cell cycle, which is known to drive neuronal death. In my preliminary analyses, I have identified prospero and staufen, two proteins that orchestrate the expression and silencing of genes that maintain terminal neuronal differentiation, among the top ten significantly downregulated genes in brains of a Drosophila model of tauopathy. In addition, I also identified 51 genes that are differentially expressed in tau transgenic Drosophila that are known to be regulated by prospero and staufen, suggest that pathogenic tau may disrupt the cellular program that maintains terminal neuronal differentiation. In addition, previously identified cellular phenotypes in tauopathy share many overlapping phenotypes with dedifferentiated cancerous cells and neural stem cells, including presence of nuclear envelope invaginations, heterochromatin decondensation, expression of development-associated genes, and cell cycle activation. In this proposal, I will test the hypothesis that pathogenic tau leads to neuronal death by dysregulating prospero and staufen, thereby disrupting the cellular program that maintains terminal neuronal differentiation in neurons. In Aim I, I will determine the mechanistic cause and downstream consequences of prospero depletion. In Aim 2, I will determine if loss of terminal neuronal differentiation mediates neuronal death in tau transgenic Drosophila. In Aim 3, I will determine whether maintaining neuronal differentiation is a viable therapeutic strategy for preventing neuronal death in tauopathy. My findings will identify new targets for therapeutic development for AD and related tauopathies, as well as other disorders involving loss of terminal differentiation.